Levopro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOPRO® (LEVOPRO®)

Composition:

Active substance: levofloxacin;

100 ml of solution contains levofloxacin hemihydrate equivalent to 500 mg of levofloxacin;

Excipients: anhydrous glucose, disodium edetate, hydrochloric acid diluted, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties:

At release: clear light-yellow solution.

For shelf life: clear solution ranging from light-yellow to light-brown in color.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones, the S(-) enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action. Levofloxacin, as a fluoroquinolone antibacterial agent, acts on the DNA gyrase and topoisomerase IV complex.

Pharmacokinetic/pharmacodynamic relationship. The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the pharmacokinetic concentration–time curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance. The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones. Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.

Breakpoints.

The recommended breakpoints for levofloxacin MIC values, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from moderately susceptible (intermediate) and resistant organisms, are shown in Table 1.

Table 1

Clinical breakpoints for levofloxacin MIC (version 10.0, 01-01-2020)

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 0.5 mg/l	> 1 mg/l
Pseudomonas spp.	≤ 0.001 mg/l	> 1 mg/l
Acinetobacter spp.	≤ 0.5 mg/l	> 1 mg/l
Staphylococcus spp. coagulase-negative	≤ 0.001 mg/l	> 1 mg/l
Enterococcus spp.1	≤ 4 mg/l	> 4 mg/l
S. pneumoniae	≤ 0.001 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 0.001 mg/l	> 2 mg/l
H. influenzae	≤ 0.06 mg/l	> 0.06 mg/l
M. catarrhalis	≤ 0.125 mg/l	> 0.125 mg/l
Helicobacter pylori	≤ 1 mg/l	> 1 mg/l
Aerococcus sanguinicola and urinae2	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
Pharmacokinetic/pharmacodynamic breakpoints (non-species related)	≤ 0.5 mg/l	> 1 mg/l

1 Only uncomplicated urinary tract infections.

2 Susceptibility depends on sensitivity to ciprofloxacin.

Resistance prevalence may vary geographically and over time for individual species. Local information on resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the benefit of the agent at least questionable for certain types of infections.

Typically sensitive species

Aerobic Gram-positive bacteria:

Bacillus anthracis, Staphylococcus aureus methicillin-sensitive*, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic Gram-negative bacteria:

Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria:

Peptostreptococcus.

Others:

Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species that may develop resistance

Aerobic Gram-positive bacteria:

Enterococcus faecalis, Staphylococcus aureus methicillin-sensitive*, coagulase-negative Staphylococcus spp.

Aerobic Gram-negative bacteria:

Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria:

Bacteroides fragilis.

Naturally resistant strains

Aerobic Gram-positive bacteria:

Enterococcus faecium.

* Methicillin-resistant Staphylococcus aureus is likely to be cross-resistant to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations reached within 1–2 hours. Absolute bioavailability is approximately 99–100%.

Food has almost no effect on the absorption of levofloxacin.

Steady state is achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution.

Approximately 30–40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is about 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into tissues and body fluids.

Levofloxacin has the ability to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation.

Levofloxacin undergoes minimal metabolism; metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination.

After oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). Total clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating interchangeability of these routes (oral and intravenous).

Linearity.

Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 1000 mg.

Special patient groups.

Patients with renal impairment

Impaired renal function affects the pharmacokinetics of levofloxacin. With decreased renal function, renal excretion and clearance are reduced, and elimination half-life is prolonged, as shown in Table 2 below.

Table 2

Pharmacokinetics in renal impairment after a single oral 500 mg dose

Creatinine clearance (mL/min)	< 20	20–49	50–80
Renal clearance (mL/min)	13	26	57
Elimination half-life (hours)	35	27	9

Geriatric patients.

There are no significant differences in the pharmacokinetics of levofloxacin in younger and elderly patients, except for differences related to creatinine clearance.

Gender differences.

Separate analysis of female and male patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the drug:

• Community-acquired pneumonia*;
• Complicated skin and soft tissue infections*;
• Acute pyelonephritis and complicated urinary tract infections;
• Chronic bacterial prostatitis;
• Inhalational anthrax: post-exposure prophylaxis and treatment.

* For the indicated infections, levofloxacin should be prescribed only when the use of other antibacterial agents, which are usually recommended for initial treatment of these infections, is inappropriate or impossible.

Official guidelines on the appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to levofloxacin, other fluoroquinolones, or to any other component of the medicinal product;
• Epilepsy;
• Tendon damage associated with prior use of fluoroquinolones;
• Pregnancy or breastfeeding;
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs)

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, nonsteroidal anti-inflammatory drugs, or other substances that lower the seizure threshold. The concentration of levofloxacin is approximately 13% higher when administered with fenbufen than when levofloxacin is taken alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid. This is because both drugs can block tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that these statistically significant kinetic differences would have clinical significance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Other information.

The following medicinal products do not have any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly: calcium carbonate, digoxin, glyburide (glibenclamide), ranitidine.

Effect of levofloxacin on other medicinal products.

Cyclosporine.

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists.

When used concomitantly with vitamin K antagonists (e.g., warfarin), increases in coagulation parameters (prothrombin time/international normalized ratio) and/or bleeding events, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concurrently (see section "Special precautions for use").

Medicinal products that prolong the QT interval.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic agents) (see section "Special precautions for use" (QT interval prolongation)).

Glucocorticoids. The risk of tendon rupture is increased when levofloxacin is used concomitantly with glucocorticoids.

Other significant information.

No effect of levofloxacin on the pharmacokinetics of theophylline (a substrate of the CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.

Concomitant use of levofloxacin with alcohol is not recommended.

Special precautions for use.

The use of this medicinal product should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients with levofloxacin should only be initiated if there are no alternative treatment options and after careful benefit-risk assessment.

An aneurysm/dissection of the aorta and valvular regurgitation/incompetence.

Epidemiological data suggest an increased risk of developing aortic aneurysm or dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use.

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/incompetence of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a family history of aneurysm or congenital heart valve defects, patients diagnosed with aneurysm and/or aortic dissection or with heart valve disease, and in patients with other risk factors such as:

• risk factors for both aortic aneurysm/dissection and valvular regurgitation/incompetence: connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis;
• risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren’s syndrome;
• risk factors for valvular regurgitation/incompetence: infective endocarditis.

The risk of aortic aneurysm, dissection, and rupture is increased in patients receiving systemic corticosteroids concomitantly.

In the event of sudden abdominal pain, chest pain, or back pain, patients should seek immediate emergency medical attention.

Patients should be advised to seek immediate medical help if they experience acute shortness of breath, a new episode of palpitations, or the development of abdominal swelling or swelling of the lower limbs.

Resistance risks

Methicillin-resistant Staphylococcus aureus (MRSA) is often also resistant to fluoroquinolones, including levofloxacin. Thus, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin.

Resistance to fluoroquinolones in Escherichia coli (the most common cause of urinary tract infections) varies across different countries. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.

Pulmonary form of anthrax

Clinical practice is based on in vitro susceptibility studies of Bacillus anthracis, experimental animal data, and limited human data. Physicians should refer to nationally and/or internationally agreed guidelines for the treatment of anthrax.

Duration of infusion

The recommended duration of infusion should be at least 30 minutes for a 250 mg dose or 60 minutes for a 500 mg dose of levofloxacin infusion solution. Tachycardia and transient lowering of blood pressure have been observed during ofloxacin infusion. Rarely, severe hypotension may lead to cardiovascular failure. If a significant drop in blood pressure occurs during levofloxacin (the L-isomer of ofloxacin) infusion, administration of the drug should be immediately discontinued.

Tendinitis and tendon rupture.

Tendinitis may occur in individual patients. Development of tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within the first 48 hours of initiating quinolone or fluoroquinolone therapy, and such cases have also been reported several months after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with levofloxacin should be immediately discontinued and alternative treatment options considered. Affected limbs should be appropriately managed (e.g., immobilization). Corticosteroids are not recommended in cases of tendinopathy.

Myoclonus

Cases of myoclonus have been reported in patients treated with levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be immediately discontinued at the first signs of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease.

Diarrhea, especially severe, persistent, or bloody diarrhea, during or after treatment (including several weeks after treatment) with levofloxacin may be a symptom of Clostridium difficile-associated disease (CDAD), which can range from mild to life-threatening. The most severe form is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be immediately discontinued and symptomatic and specific treatment (e.g., vancomycin) promptly initiated. In such cases, drugs that inhibit intestinal motility are contraindicated.

Patients with predisposition to seizures.

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures, such as those with pre-existing central nervous system disorders, concomitant therapy with phenylbutazone or similar non-steroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs (see section "Adverse reactions"), levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis is required.

Patients with renal impairment.

Since levofloxacin is primarily excreted via the kidneys, dose adjustment is necessary in patients with impaired renal function (renal insufficiency) (see section "Method of administration and dosage").

Hypersensitivity reactions.

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., from angioneurotic edema to anaphylactic shock), occasionally after the first dose (see section "Adverse reactions"). If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin adverse reactions.

Severe skin adverse reactions, including toxic epidermal necrolysis (TEN, also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use and may be life-threatening or fatal (see section "Adverse reactions").

Patients should be informed about signs and symptoms of severe skin reactions that may occur after drug administration and should be closely monitored. If signs or symptoms suggestive of these reactions appear, levofloxacin should be immediately discontinued and alternative treatment considered.

If a patient develops a serious reaction such as SJS, TEN, or DRESS syndrome after levofloxacin use, levofloxacin treatment should never be prescribed to this patient again.

Disturbances in glucose metabolism.

As with all quinolones, cases of altered blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, typically in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section "Adverse reactions"). The medicinal product contains 5 mg of glucose per dose (100 ml vial), so it should be used with caution in patients with diabetes mellitus.

If a patient reports abnormal blood glucose levels, treatment should be immediately discontinued and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Prevention of photosensitization.

Cases of photosensitization have been reported with levofloxacin use (see section "Adverse reactions"). To prevent photosensitization, patients are advised to avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., sunlamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists.

Due to the potential for increased coagulation parameters (prothrombin time/international normalized ratio) and/or increased frequency of hemorrhagic complications in patients receiving levofloxacin in combination with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychiatric disorders or a history of psychiatric illness.

QT interval prolongation.

Fluoroquinolones, including levofloxacin, should be used cautiously in patients with known risk factors for QT interval prolongation, such as:

• congenital or acquired long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Method of administration and dosage (Elderly patients)", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used cautiously in these patient groups.

Peripheral neuropathy.

Cases of sensory or sensorimotor peripheral neuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients taking fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, to prevent irreversible damage.

Hepatobiliary disorders.

Cases of liver necrosis up to hepatic failure with fatal outcome have been reported with levofloxacin use (mainly in patients with severe underlying conditions such as sepsis) (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Acute pancreatitis.

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the typical symptoms of acute pancreatitis. Patients who develop nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should be examined immediately by a physician. If acute pancreatitis is suspected, levofloxacin should be discontinued and, if confirmed, not restarted. Caution is advised when treating patients with a history of pancreatitis (see section "Adverse reactions").

Blood system disorders.

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may occur during levofloxacin treatment (see section "Adverse reactions").

If any of these blood disorders are suspected, blood parameters should be monitored. If abnormalities are detected, discontinuation of levofloxacin therapy should be considered.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including fatalities and cases requiring respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If any visual disturbances or ocular adverse reactions occur during levofloxacin intake, patients should immediately consult an ophthalmologist (see sections "Adverse reactions" and "Ability to influence reaction rate when driving or operating machinery").

Superinfection.

The use of levofloxacin, particularly prolonged use, may lead to overgrowth of organisms not susceptible (resistant) to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results.

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate screening results may require more specific testing methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.

Long-term, disabling, and potentially irreversible serious adverse reactions.

In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors, have reported long-term (lasting months or years), disabling, and potentially irreversible adverse reactions affecting various, and sometimes multiple simultaneously, organ systems (e.g., musculoskeletal, nervous, psychiatric, and sensory organs). The drug should be immediately discontinued at the first sign or symptom of any serious adverse reaction, and medical advice should be sought.

Sodium.

This medicinal product contains 39.1 mmol (900 mg) of sodium per 100 ml of solution. This should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Due to the lack of studies and the potential for quinolone-induced damage to joint cartilage in the growing organism, the drug is contraindicated in pregnant and breastfeeding women. If pregnancy is diagnosed during treatment, this should be reported to the physician.

Levofloxacin did not cause impairment of fertility or reproductive function in animal studies.

Ability to influence reaction rate when driving or operating machinery.

The medicinal product has a minor or moderate effect on the ability to drive or operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient’s ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are critical (e.g., driving or operating machinery).

Method of Administration and Dosage

The drug should be administered intravenously, slowly, once or twice daily. Dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the drug. Treatment with the drug after initial use of its intravenous form may be completed with the oral formulation, provided such therapy is appropriate for the individual patient. Due to the bioequivalence of parenteral and oral dosage forms, equivalent doses may be used.

The infusion duration should be at least 30 minutes for 250 mg or 60 minutes for 500 mg of solution (see section "Special Instructions").

Dosage for patients with normal renal function, in whom creatinine clearance exceeds 50 ml/min

Table 3

Indications	Dose, mg	Number of doses per day	Treatment duration1
Community-acquired pneumonia	500	1–2 times	7–14 days
Acute pyelonephritis	500	1 time	7–10 days
Complicated urinary tract infections	500	1 time	7–14 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1–2 times	7–14 days
Pulmonary form of anthrax	500	1 time	8 weeks

1 The duration of treatment includes intravenous and oral administration. The time to switch from intravenous to oral administration depends on the clinical condition, but usually takes from 2 to 4 days.

Dosage for patients with impaired renal function in whom creatinine clearance is less than 50 mL/min

Table 4

Creatinine clearance	Dosing regimen (depending on severity of infection and nosological form)
	250 mg / 24 h	500 mg / 24 h	500 mg / 12 h
50–20 ml/min	initial dose — 250 mg, subsequent — 125 mg/24 h	initial dose — 500 mg, subsequent — 250 mg/24 h	initial dose — 500 mg, subsequent — 250 mg/12 h
19–10 ml/min	initial dose — 250 mg, subsequent — 125 mg/48 h	initial dose — 500 mg, subsequent — 125 mg/24 h	initial dose — 500 mg, subsequent — 125 mg/12 h
<10 ml/min (as well as during hemodialysis and CAPD1)	initial dose — 250 mg, subsequent — 125 mg/48 h	initial dose — 500 mg, subsequent — 125 mg/24 h	initial dose — 500 mg, subsequent — 125 mg/24 h

1 After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Dosing in elderly patients. If renal function is not impaired, there is no need for dose adjustment.

The medicinal product should be used immediately (within 3 hours) after piercing the rubber stopper to prevent bacterial contamination. Protection from light during infusion is not required. The medicinal product is intended for single use only.

The solution should be inspected visually before use. Only clear solution free from particles should be used.

Any unused medicinal product should be disposed of in accordance with current requirements.

Mixing with other infusion solutions

The medicinal product is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose solution for injection;
• 2.5% glucose in Ringer's solution;
• combined solutions for parenteral nutrition (amino acids, glucose, electrolytes).

For incompatibilities, see section "Incompatibilities".

Children.

Levofloxacin is contraindicated in children (under 18 years of age) due to the potential risk of damage to articular cartilage.

Overdose.

Based on toxicity studies in animals and clinical and pharmacological studies using doses higher than therapeutic, the most serious adverse events expected following acute overdose of levofloxacin infusion solution are central nervous system (CNS) effects such as confusion, dizziness, altered consciousness, seizures, and QT interval prolongation.

During postmarketing surveillance, the following CNS adverse effects have been observed: confusion, convulsions, myoclonus, hallucinations, and tremor.

Treatment. In case of overdose, symptomatic treatment should be administered. ECG monitoring is required due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), is not effective in removing levofloxacin from the body. There are no specific antidotes available.

Adverse reactions.

The adverse reactions listed below are categorized by organ systems and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), frequency not known (cannot be estimated based on available data). Within each frequency group, adverse events are listed in order of decreasing severity.

Body systems	Common	Uncommon	Rare	Frequency unknown
Infections and infestations		Fungal infections, including infections caused by Candida species. Resistance of pathogenic microorganisms
Blood and lymphatic system disorders		Leukopenia Eosinophilia	Thrombocytopenia Neutropenia	Bone marrow dysfunction (including aplastic anemia) Pancytopenia Agranulocytosis Hemolytic anemia
Immune system disorders			Angioedema (Quincke's edema) Increased sensitivity	Anaphylactic shock1 Anaphylactoid shock1
Metabolism and nutrition disorders		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus	Hypoglycemic coma Hyperglycemia
Psychiatric disorders*	Insomnia	Anxiety Confusion Nervousness	Psychotic reactions (e.g., with hallucinations, paranoia) Depression Agitated state Sleep disturbances Nightmares Delirium	Psychotic disorders with behavior dangerous to the patient, including suicidal thoughts or suicide attempts, mania
Nervous system disorders*	Headache Dizziness	Somnolence Tremor Dysgeusia	Seizures Paraesthesia	Peripheral sensory neuropathy Peripheral sensory motor neuropathy Parosmia, including anosmia Dyskinesia Extrapyramidal disorders Ageusia Syncope Benign intracranial hypertension Myoclonus
Eye disorders*			Visual disturbances, such as blurred vision	Transient loss of vision
Ear and labyrinth disorders*		Vertigo	Tinnitus	Hearing loss Worsening of hearing
Cardiac disorders**			Tachycardia Palpitations	Ventricular tachycardia, which may lead to cardiac arrest Ventricular arrhythmia and torsades de pointes (mainly observed in patients with risk factors for QT interval prolongation), QT interval prolongation as measured by ECG
Vascular disorders**	Applies only to intravenous formulations: Phlebitis		Arterial hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm, allergic pneumonitis
Gastrointestinal disorders	Diarrhea Vomiting Nausea	Abdominal pain Dyspepsia Flatulence Constipation		Hemorrhagic diarrhea, which rarely may be a sign of enterocolitis, including pseudomembranous colitis Pancreatitis
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated blood bilirubin levels		Jaundice and severe liver injury, including cases of fatal acute liver failure, primarily in patients with severe underlying diseases Hepatitis
Skin and subcutaneous tissue disorders2		Rash Pruritus Urticaria Hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Persistent drug eruptions	Toxic epidermal necrolysis Stevens-Johnson syndrome Polymorphic erythema Photosensitivity reactions Leukocytoclastic vasculitis Stomatitis Skin hyperpigmentation
Musculoskeletal and connective tissue disorders*		Arthralgia Myalgia	Tendon disorders, including tendinitis (e.g., Achilles tendon) Muscle weakness, which may be significant in patients with myasthenia gravis	Acute skeletal muscle necrosis Tendon rupture (e.g., Achilles tendon) Ligament rupture Muscle rupture Arthritis
Renal and urinary disorders		Increased blood creatinine levels	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions*	Applies only to intravenous formulations: Infusion site reaction (pain, redness)	Asthenia	Chills	Pain (including back, chest, limb pain)
Endocrine disorders			Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

1 Anaphylactic and anaphylactoid reactions may occasionally occur even after administration of the first dose of the drug.

2 Mucous membrane reactions may occasionally occur even after administration of the first dose of the drug.

* In very rare cases, in patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, prolonged (for months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems and sensory organs (such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disorders) have been reported (see section "Special precautions"); anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances have also been reported as potential aspects of prolonged and disabling adverse reactions caused by fluoroquinolones.

Other adverse effects associated with the use of fluoroquinolones include porphyria attacks in patients with porphyria.

** Cases of aneurysm and dissection of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have occurred in patients receiving fluoroquinolones (see section "Special precautions").

Shelf life.

2 years.

Incompatibility.

The medicinal product should not be mixed with infusion solutions and injections that are physically and chemically unstable at pH 3–4 (such as sodium bicarbonate, penicillin, heparin).

It should not be mixed with other medicinal products in the same container, except as specified in the section "Method and dosage of administration".

Storage conditions.

Store in a dry, protected from light place at a temperature not exceeding 25°C. Keep out of reach of children. Do not freeze.

Packaging. 100 ml or 150 ml in a container; 1 container in a polyethylene bag in a carton.

Prescription category. Prescription only.

Manufacturer.

Subsidiary enterprise "Farmatreyd".

Manufacturer's address and location of business activity.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.